Off-Label Use of Prescription Drugs

A recent survey of 599 primary care physicians and 600 psychiatrists found that:

The adjusted response rate was 47%, respondents were similar to non-respondents, and physicians commonly prescribed the drugs examined. The average respondent accurately identified the FDA-approval status of just over half of the drug-indication pairs queried (mean 55%; median 57%). Accuracy increased modestly (mean 60%, median 63%) when limited to drugs the respondent reported having prescribed during the previous 12 months. There was a strong association between physicians’ belief that an indication was FDA-approved and greater evidence supporting efficacy for that use (Spearman’s 0.74, p < 0.001). However, 41% of physicians believed at least one drug-indication pair with uncertain or no supporting evidence (e.g., quetiapine [Seroquel®] for dementia with agitation) was FDA approved.

These results are interesting, but deserve to be dissected a bit further. Taken at face value they indicate that physicians need better education regarding the FDA indications and (more importantly) the evidence-base for commonly prescribed drugs. This is an uncontroversial recommendation, and I personally strongly advocate more thorough physician continuing medical education.

Of course, at SBM we have to also dissect the weaknesses of any study we examine. This was a voluntary survey with a 47% response rate, which opens the door for significant responder bias. The survey does not broadly represent different specialties and therefore its relevance beyond primary care and psychiatry is uncertain. The details of the study may also have greatly influenced the outcome.

For example, one of the drug-indication pairs was gabapentin for diabetic peripheral neuropathy. Gabapentin is not specifically indicated for diabetic neuropathy, but it is indicated for post-herpetic neuralgia. Both conditions are forms of neuropathic pain, and it is highly scientifically plausible for a treatment of one condition to also be effective for the other. In fact, there is strong evidence that gabapentin is effective for diabetic neuropathy, and it is commonly prescribed for this condition (in fact insurance companies often require that it is first line treatment as it is now available generically and is therefore less expensive than newer drugs that are indicated specifically for diabetic neuropathy). In other words, this was one of the easiest mistakes to make.

The most cautionary result of this survey is the fact that 41% of responders belief in a drug-indication pair that is not evidence-based. But the example given (to put it into perspective – quetiapine for dementia with agitation) is not indicated not because quetiapine is not used for that type of problem but because it should not be used in patients with dementia. This is the kind of detail a prescriber should know.

So how do we put the results of this survey into perspective? I think they do indicate the need for better physician education regarding the drugs they prescribe -and to put that information at their fingertips at the point of patient care. However, the drug-interaction pairs assessed involved a mixture of subtle but important distinctions and insignificant ones.

It is important to recognize that off-label use of medication is not the same as non-evidence-based used of medications. In fact, the gabepentin-diabetic neuropathy example is my personal favorite to make this point. Some argue that physicians are better off knowing the evidence-base for a drug rather than the FDA regulations – which are about marketing, not about use (the FDA regulates the marketing of drugs, but once on the market the FDA does not regulate how physicians prescribe drugs). On the other hand, knowing that a drug is approved for a specific indication is a reliable indicator that it has passed the rather high bar of evidence for safety and efficacy required by the FDA.

Off label use of medications is not uncommon. A 2001 review indicates that 21% of prescriptions are for off-label use. Actually, I thought the number was higher – 21% seems quite reasonable to me. But what is more important is the evidence base for this off-label use. The same article indicates that 73% of off-label use has little or no scientific support. That is high – however, there are many assumptions hidden in this number.

Much of off-label use includes prescribing a drug for an approved indication but not in an approved population. For example, this includes prescribing drugs studied in adults only to a pediatric population. If the drug has not been studied in children this can be considered without scientific support.There are very real concerns about how to apply the literature to the pediatric population, and this does highlight the need for more research in children – but it should not be confused with prescribing a drug for an indication for which there is no evidence.

Off-label prescribing also includes prescribing a class of drugs for a class of disorders – such as prescribing a sodium-channel blocker for neuropathic pain (rather than a specific sodium-channel blocker for a specific cause of neuropathic pain). It can be reasonably debated how to assess the evidence base for such class use of drugs.

There are risks and benefits to off-label use of drugs. Dr. G. Caleb Alexander summarizes them here:

Disadvantages of off-label use

* May diminish public expectation that drugs will be evaluated for safety and efficacy before use
* Blunts industry incentives to perform studies required for FDA label changes
* Drugs used off label may have unrecognized safety and efficacy problems
* Promotes use of drugs in populations (e.g., children, the elderly) for which they have not been tested

Advantages of off-label use

* Allows for clinical innovation, especially for patients who do not respond to standard treatments
* May be only available option for uncommon conditions or for patient populations that have not been studied
* Allows physicians to anticipate growing evidence of efficacy prior to formal evaluation
* Increases return on investment for pharmaceutical firms

I would add under advantages that off-label use of drugs allows for evidence-based options for which (for economic reasons) the pharmaceutical company did not seek FDA approval. Some of these uses may be life-saving.

Conclusion

In my opinion, focusing on FDA indications for a drug is a bit of a distraction. The real issue is the evidence for safety and efficacy for any specific application of a pharmaceutical (or any intervention, for that matter). FDA approval is all about marketing, not about the appropriateness of use. Knowing what a drug is indicated for is a useful shortcut to knowing that it is safe and effective for that indication. It is also essential to be familiar with the FDA package insert – which contains information on side effects, contraindications, and drug-drug interactions.

And as I stated above, while physicians are generally familiar with the drugs they most prescribe, there is room for improvement in terms of physician education and access to information at the point of patient care. Technology is helping with the latter issue, but other steps may be required to improve physician knowledge, such as more effective use of continuing medical education requirements.

Focusing too myopically on the issue of off-label use, however, is misleading and not constructive.

Posted by Steven Novella

Founder and currently Executive Editor of Science-Based Medicine Steven Novella, MD is an academic clinical neurologist at the Yale University School of Medicine. He is also the host and producer of the popular weekly science podcast, The Skeptics’ Guide to the Universe, and the author of the NeuroLogicaBlog, a daily blog that covers news and issues in neuroscience, but also general science, scientific skepticism, philosophy of science, critical thinking, and the intersection of science with the media and society. Dr. Novella also has produced two courses with The Great Courses, and published a book on critical thinking - also called The Skeptics Guide to the Universe.